The HIV-1 reservoir is a small pool of persistent long-lived and latently infected resting memory CD4 T cells that persist by exploiting mechanisms similar to those used by hematopoietic and cancer stem cells. Eradication of this reservoir in intravenous drug users is a critical step to be conquered to develop a cure for this disease. We have shown that homeostatic and antigen- induced proliferation are critical for the maintenance of this reservoir by promoting the survival of latently infected transitional and central memory CD4 T cells, respectively. Hence therapeutic strategies that solely use antiviral molecules will never purge the reservoir. We will test the hypothesis using a system biology approach that the mechanisms that control long term T cell memory overlap with those that control the size and persistence of this reservoir. We will investigate in aim 1 the implication of both mechanisms in the maintenance of the HIV reservoir by identifying the size, the localization and the diversity of the HIV reservoir in longitudinal samples of successfully treated patients who received a therapeutic vaccine that triggers TCR or IL-7 a cytokine that induces homeostatic proliferation of CD4 T cells and in a primate model.. In aim 2 we will use siRNAs and dominant negative mutants to knock down genes, i.e. stat 5a, FOXO3a and the wnt/Notch pathways, ex vivo and in vivo all involved in the self renewal of memory T cells. In aim 3 we will identify genes and pathways regulated by Histone Deacytilase inhibitors. Genome wide siRNA and small molecule approaches will be used to silence relevant pathways and identify those that result in purging the HIV reservoir. We will identify pathways that can be targeted to purge HIV from its reservoir. This will lead to the development of novel immunological interventions in the treatment of HIV.